Remodeling the Proteostasis Network to Rescue Glucocerebrosidase Variants by Inhibiting ER-Associated Degradation and Enhancing ER Folding

• DOI: 10.1371/journal.pone.0061418
• Publication Date: 2013-04-19T21:10:35Z
• Authors: Fan Wang; Laura Segatori
• Keywords: Proteostasis; Endoplasmic-reticulum-associated protein degradation

Gaucher's disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize protein's native folding leading to ER-associated degradation (ERAD) misfolded enzyme. Enhancing cellular capacity remodeling proteostasis network promotes and activity mutated variants. However, modulators reported so far, including ERAD inhibitors, trigger stress lead induction apoptosis. We show herein that lacidipine, an L-type Ca2+ channel blocker also inhibits ryanodine receptors on ER membrane, enhances folding, trafficking most severely destabilized variant achieved via inhibition fibroblasts derived from patients with GD. Interestingly, reprogramming combining modulation homeostasis remodels unfolded protein response dramatically lowers apoptosis typically associated inhibition.